Transcriptional-translational conflict in bladder epithelial homeostasis and cancer

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ABSTRACT Chromatin remodeling and protein synthesis are tightly regulated processes that impact gene expression and cellular phenotypes. However, it is unknown to what extent these two regulatory mechanisms may be linked or independent in controlling normal epithelial physiology and disease states. We have uncovered a new functional relationship between the chromatin remodeler ARID1A and mRNA translation elongation. This link is involved in maintaining cellular fitness in the context of bladder carcinogenesis and represents a new tumor suppressive mechanism we call transcriptional-translational conflict. Loss of ARID1A triggers a simultaneous increase in oncogenic transcripts, but also inhibition of the translation elongation factor eEF2, which results in a reduction in protein synthesis and prevents cancer pathogenesis. However, this process can be reversed by restoring translation elongation, which enables the efficient synthesis of oncogenic mRNAs and cancer progression. This finding provides a unified gene expression model which explains why ARID1A is a context specific tumor suppressor. Importantly, ARID1A deficient tumors retain a sensitivity to pharmacologic inhibition of translation elongation initiation. Recently, our laboratory has developed and characterized new in vitro and in vivo models of both human and murine ARID1A deficient bladder cancer where we can also toggle translation elongation. We have used these models to discover a critical link between ARID1A and the process of mRNA translation elongation that is vital for urothelial homeostasis and bladder cancer progression. We hypothesize that transcriptional-translational conflict in urothelium lacking ARID1A is mediated through decreased eukaryotic elongation factor 2 (eEF2) activity, which when reversed unleashes a poised druggable oncogenic program sufficient to drive cancer progression. Our long-term objective is to utilize state-of-the-art mouse models and primary organoid systems, whole transcriptome polysome profiling, and patient derived xenografts to definitively investigate the fundamental link between ARID1A and protein synthesis regulation in a highly relevant population of bladder cancer patients. To do so, we will address the following aims: 1) Determine the relevance and mechanism of transcriptional-translational conflict in urothelial cell transformation and carcinogenesis; and 2) Elucidate how gene expression parity enables cancer progression and represents a context specific therapeutic vulnerability. This research will help us gain a deeper understanding of the biology of bladder cancer and open a new paradigm for treating patients with lethal disease. Our work is particularly important for the progress of precision medicine because it seeks to mechanistically tie a highly prevalent bladder cancer genotype (ARID1A loss) to a new treatment modality that holds therapeutic promise for bladder cancer patients.